The term oral anticoagulant (OAC) tends nowadays to be used in guidance to mean warfarin and its class whilst aspirin is antiplatelet or antithrombotic. The new agents are referred to as novel oral anticoagulants (NOACs). All anticoagulants are contraindicated in liver failure, patients with uncontrolled hypertension or bleeding risk. Their use is cautioned in renal impairment. Bleeding risks increase with patient age and comorbidity. There are numerous drug interactions and this article hopes to familiarise GPs with available agents, many of them very new, and remind them to refer to the BNF when prescribing. All patients on any form of anticoagulant should be reviewed at least annually to check that their presumed health has not altered. GPs are in a great position to help patients make best judgements about the suitability of medication long-term.
Aspirin, salicylic acid
Aspirin is an antiplatelet drug, found naturally in the bark of the white willow tree, the same tree used to produce cricket bats. It had been known about in the UK since the 1850s. It is available over-the-counter (OTC) and GPs should ask patients about self medication. Prostaglandins (PGs), thromboxaneA2 and prostacyclin act to promote clotting by vasoconstriction, platelet aggregation and activation and are produced via an enzyme called cyclo-oxygenase (COX) after cell injury. Aspirin and NSAIDs, like ibuprofen, inhibit COX to prevent formation of these PGs, prostacyclin and thromboxane and so reduce platelet aggregation and activation and can promote bleeding. Aspirin irreversibly inhibits COX and so acts for about 10 days until the platelets are replaced in the body. NSAIDs reversibly inhibit COX. Aspirin is also antipyretic and anti-inflammatory, again via reduction in prostaglandin synthesis. It is the most commonly prescribed anti-thrombotic and costs the NHS £27,767,900 per annum.1
Side-effects: Aspirin, like NSAIDs, is associated with peptic ulceration and gastro-intestinal (GI) bleeding. A systematic review of GI bleeding suggested that 9% of cases were related to aspirin or NSAID use and the mortality rate in those patients is about 20%, mainly in the elderly.2 This risk is increased when combined with steroids, other NSAIDs and other anticoagulants.
Tests: Aspirin prolongs the bleeding time due to its antiplatelet action and this explains the increased mortality rate compared to non-aspirin patients with GI bleeding. Aspirin should be stopped several days before planned surgery. There is a normal PT time, aPTT and platelet count.
• Acute myocardial infarction (MI). GPs should administer 300mg stat dose of aspirin to patients who appear to have acute MI chest pain and send a written record with the patient to the hospital. Other anti-platelets are not recommended.3 NICE also suggests GTN as long as the patient is not too hypotensive, a resting ECG if possible and pulse oximetry-giving oxygen if the stats are below 94% and the patient does not exist on a hypoxic drive whilst awaiting the ambulance.
• Acute STEMI, NSTEMI and unstable angina (UA)
• Secondary prevention of CHD usually at 75mg a day long-term if tolerated4 and is reflected in Quality and Outcomes Framework (QoF) indicators CHS 005 and CHD 006 suggesting aspirin use in patients with CHD or a history of MI who have no contraindications or significant comorbidities.
• Chronic heart failure at a dose of 75-150mg in patients if they are in sinus rhythm and have atheroma.5
• Post coronary artery bypass graft (CABG).
• Chronic kidney disease (CKD)-to prevent death from CHD if there are no contraindications.6 The evidence for benefit of aspirin medication in patients at end stage renal failure (ESRF) is lacking at present but is present in CKD 3.7 CKD patients have thrombotic tendencies and are more likely to die of CHD, they have higher levels of thrombin and fibrinogen and F7 and 13. Also. however. they have increased bleeding tendencies with anaemia, platelet dysfunction, endothelial and vWF abnormalities.
• Acute thrombotic CVA and transient ischaemic attacks (TIA) in secondary care at a dose of 300mg a day first line once haemorrhage has been excluded. A patient with disabling CVA due to atrial fibrillation (AF) will receive two weeks of aspirin 300mg a day and then be changed to warfarin long-term unless contraindicated. If the patient is in sinus rhythm it depends on previous drug use and causes but the patient may be given long-term aspirin and dipyridamole.8
• Diabetics above 50 years old with a blood pressure below 145/90mmHg are recommended to take long-term low dose aspirin as primary prevention of CHD9 in the 2010 guidance but Diabetes UK only recommends it for high risk patients.
• Peripheral arterial disease (PAD) affects 20% of the over 60s and is more likely in smokers, diabetics and patients with other atheroma,10 again low dose aspirin is recommended as secondary prevention- QoF indicator PAD004. There is an increased risk of bleeding post-operatively in patients having arterial bypass grafts on warfarin compared to aspirin and so aspirin is recommended for patients having bypass grafting for PAD.
Proton pump inhibitors (PPIs) are recommended in patients who develop some heartburn on aspirin. There has been recent publicity about the increased risk of C. Difficile infection in patients on PPIs and suggestion of a causal link. A recent review of the literature suggested that over 3000 patients in the community would need to take a PPI to cause harm via C. diff.11 and the GPs may want to target long-term use of PPIs in patients who may be hospitalised frequently (eg. severe COPD) patients if they are not required.
Warfarin, a coumarin or VKA
Warfarin was discovered in the 1920s when cattle died from haemorrhage after eating mouldy sweet clover in a field. It was used as a rat poison for many years before finding a human therapeutic use.12
Warfarin is our most commonly used oral anticoagulant and despite being used less than aspirin, costs almost as much at £24,674,800 in prescription costs alone.1 NICE refers to warfarin as a VKA, vitamin K antagonist, in some of its clinical guides. Other drugs in this group are acenocoumarol (Sinthrome) and phenindione.13 It produces defective clotting factors by acting as an antagonist of vitamin K (phytomenadione). Warfarin and other coumarins block the action of vitamin K epoxide reductase,14 resulting in decreased concentrations of vitamin K in tissues and an inability to produce a number of active clotting factors; the clotting factors then no longer bind stably to blood vessel endothelium and cannot activate clotting. It takes 48-72 hours for warfarin to take effect so heparin is given sometimes to cover the delay eg. in DVT and PE therapy. INR targets vary from 2-4 depending on the indication. It is impossible to accurately predict the correct dose of warfarin for desired suppression of clotting so treatment must be carefully monitored to avoid overdosing.
Side effects: A review in 2009 found that in the UK there was an overall prescribing error rate of 7.5% and one in 15 hospital admissions were medication related. Because of its narrow therapeutic range and serious side-effect of bleeding, warfarin appears in the top 10 of adverse side-effect causing drugs.15 Indeed aspirin and NSAIDs are also in the top 10. In the USA anticoagulants ranked first in 2004 in the number of total mentions of deaths in which drugs had caused adverse effects in therapeutic use. The estimated incidence of major bleeding has been estimated at 10-16%.16
Other side-effects are rare such as rash, diarrhoea and jaundice. 0.01-0.1% of patients on warfarin may develop skin necrosis due to thrombosis in the skin, especially if they have protein C, protein S or antithrombin deficiencies.17 This is because warfarin initially reduces the production of these natural anticoagulants and so thrombosis may occur. Protein C deficiency occurs in one in 200-500 people, protein S in one in every 500 people and antithrombin deficiency is much rarer.18
Interactions: Warfarin is metabolised in the liver by the large number of enzymes making up the p450 cytochrome complex. Other chemicals using the same process will interact and may inhibit or enhance metabolism; such as cranberry juice, metronidazole, macrolides, alcohol, amiodarone, antifungals, antiepileptic drugs, statins and many more. Broad spectrum antibiotics may reduce the amount of normal bacterial flora in the bowel. Thyroid disorders and some herbs and spices, eg. ginger and garlic, ginseng and Ginkgo biloba can interact. It is therefore imperative to ask the patient about OTC medications and check the patient's repeat script before prescribing. Warfarin should not be used in liver failure or severe renal failure but can be used at a reduced dose in mild renal impairment.13 It is contraindicated if there is a bleeding risk or uncontrolled hypertension. The balance between effective anticoagulation and bleeding risk has to be considered by the GP. A patient started on warfarin may become unreliable if prone to falls. Warfarin does not usually need to be stopped for OPC dental extractions, cataract operations, joint injections or endoscopy.19
• DVT and PE treatment. A proximal DVT ie. popliteal vein or above or PE requires warfarin for at least three months except if active cancer when LMW heparin may be preferred.
• Post embolectomy for acute arterial embolus.
• Prevention of CVA in patients awaiting cardioversion for nonvalvular AF. Secondary care may alter target INR in the weeks before and after the procedure.
• Thromboprophylaxis in patients with prosthetic heart valves.
• Thromboprophylaxis in patients with antiphospholipid syndrome.
• Thromboprophylaxis for three months in patients with tissue (bioprosthetic) heart valves post op.
• Sometimes used in dilated cardiomyopathy.
• AF-see CHADS 2 scoring but mainly anyone with AF over 65 years old who has no contraindications.
• Patients with repeated thrombotic problems despite aspirin use.
Patients on aspirin for secondary prevention of CHD may develop an indication for warfarin. The advice then is to stop the aspirin as there is no evidence of extra benefit with dual therapy. There are also a group of complex patients who require triple therapy with warfarin and two antiplatelet drugs after coronary artery stenting, perhaps if they have also had AF or DVT.
Warfarin therapy is monitored via the INR. It always causes a prolonged PT time and raised INR. It can sometimes cause prolonged bleeding time and aPTT. Computer assisted dosing is more accurate than manual dosing. Patients stable on warfarin may have a home monitor to check their own INRs and then phone the anticoagulant specialist for dosing advice. Advice is given verbally but also sent in writing or email. Also patients can be trained to take and monitor their own INRs and adjust their dose of warfarin based upon the result. A Cochrane review suggested this improved overall quality of warfarin therapy compared to usual testing in clinics without adverse effects.20 There is an excellent patient information booklet available from the DoH online.21
Action: Discovered by a medical student in 1916 heparin can be given intravenously (IV) and usually only used in severe renal disease. Low molecular weight heparins (LMWH) are those we use in practice but do not usually initiate. They are tinzaparin, enoxaparin and delteparin. Heparin activates antithrombin by binding to it and amplifies its action 100-fold. Antithrombin is sometimes called heparin cofactor and is liver synthesised. Antithrombin inactivates F10 and thrombin22 to prevent thrombus formation. Conversely, hereditary deficiency of antithrombin increases the risk of thrombosis, there are estimates that one in 20 to one in 200 patients with a DVT have antithrombin deficiency but it can be asymptomatic. The prevalence of antithrombin deficiency in the population is one in 2-3,000 people. 50% of people with antithrombin deficiency will suffer a clot in their lifetime, usually a DVT.23
Side effects: Heparin is not absorbed from the GIT so LMWH is usually given by sc injection once a day. Other side effects are HIT (heparin induced thrombocytopenia), which usually occurs in the first 14 days of use at a rate of about 0.2% and can cause thrombosis. It is less common in LMWH than in unfractionated heparin (UH) and is due to antibody formation against heparin. Rarely there may be hyperkalaemia and neutropenia. Like all anticoagulants there is a risk of bleeding, especially if the patient has severe liver disease or severe hypertension. LMWH should not be used if the eGFR is <30mls/min. LMWH is less likely than UH to cause osteoporosis but there is still an increased risk over long-term use.
Tests: aPPT is prolonged if UH is used but not if the usual LMWH is used. Bleeding time may be normal or prolonged.
• DVT or PE treatment in patients with active cancer: use LMWH for at least six months rather than warfarin.
• Initial therapy for 2-3 days in DVT or PE whilst awaiting warfarin action.
• Cerebral venous sinus thrombosis therapy.
• Bridging therapy over operations to reduce the risk of thrombus in patients stopping warfarin. There is then a reduced but still increased risk of bleeding compared to non anticoagulation.19
• Thromboprophylaxis of DVT and PE in orthopaedic lower limb surgery. There is a 21% reduction in fatal PE in patients given LMWH. It should be continued for 7-10 days but there is evidence of benefit if continued for five weeks. It is now superseded in many hospitals by specific F10 inhibitors.
• Post fractured femur and patients in lower limb plaster casts as thromboprophylaxis.
• Thromboprophylaxis in patients medically ill in hospitals who are risk assessed for morbidity and immobility.
• STEMI. The latest NICE guidance is complex, lasting 310 pages and uses a number of different antithrombotics in different scenarios. LMWH and UH feature at various points. Specifically LMWH or UH are given to patients undergoing PCI who have been treated with prasugrel or ticagrelor.23 In essence there are now a number of models of using different antithrombotics in series, LMWH, aspirin and "another" to prevent thrombus and myocardial ischaemia in patients with acute STEMI.
• ACS in secondary care until the patient is mobile.
• Post thrombotic CVA until the patient is mobile.
• During haemodialysis.
• Non septic causes of DIC to prevent consumption of clotting factors.
Action: Clopidogrel acts as an anti-platelet as it inhibits ADP receptors, which are needed for ADP in platelets to cause platelets to aggregate and bind to fibrin. Clopidogrel is a pro-drug, which is activated by the CYP450 enzyme complex at the liver. This is why some PPIs may reduce the effect of clopidogrel by increasing its liver metabolism. There is a potential for liver metabolised drug interactions. In overdose it requires platelet transfusion. There were 5,385,600 prescriptions dispensed in 20121 but new guidance will cause this to escalate.
Side effects: Rash and diarrhoea are uncommon. It is contraindicated in patients with a bleeding tendency or liver or renal impairment.
Tests: Clopidogrel does not alter the PTT and aPTT usually and more specialised tests of platelet function are needed to assess its action.
• Patients undergoing PCI: aspirin and clopidogrel can be used together. Clopidogrel in secondary care is given initially at a high loading dose to inhibit platelet aggregation. Bivalirudin in added to the combination with aspirin and clopidogrel in the treatment of adults with STEMI undergoing PCI. Clopidogrel can be one of a choice of three medications: ticagrelor and prasugrel, two NOACs, being the others given to patients having PCI.24
• STEMI for four weeks with aspirin.
• NSTEMI for 12 months with aspirin.
• Prevention of thrombosis after coronary stent.
• Alternative for patients intolerant to aspirin
• Post thrombotic CVA provided the patient is not in AF, had carotid artery surgery or coronary revascularisation.25 Now first line instead
• Patients with PAD.
• Patients with multiple areas of atheroma.
Strangely clopidogrel is not licensed for use in TIAs.
Action: Dipyridamole is a phosphodiesterase inhibitor so blocks uptake and metabolism of AMP by red blood cells and the vascular endothelium. This potentiates the anti-aggregating action of prostacyclin on platelets, causes some vasodilation and reduces thromboxane production. Thromboxane promotes platelet aggregation to produce thrombus. Dipyridamole is excreted in bile after conjugation at the liver. There were 224,300 prescriptions for asasantin retard dispensed in 2012.1
Side-effects: GIT side-effects and headache.
• Post TIA use aspirin and dipyridamole combined (asasantin retard bd)
• Post TIA use dipyridamole alone second line if the patient can't take aspirin.
• Post thrombotic CVA use asasantin retard second line if clopidogrel is not tolerated or contraindicated.
• Post thrombotic CVA use dipyridamole alone second line if aspirin and clopidogrel are contraindicated.
Novel oral anticoagulants (NOACs)
In a desire to therapeutically exploit the knowledge of the coagulation system there have been a number of NOACs developed. Some are used in the acute STEMI patients awaiting PCI and others have found a place in nonvalvular AF therapy and in DVT therapy. They are renal excreted so their dose varies in reduced kidney function. The eGFR should be estimated annually and more often if eGFR is below 60mls/min. There are published tables to estimate eGFR and recommended dosage of rivaroxaban, apixaban and dabigatran. In general the European Society of Cardiology does not recommend NOACs if the eGFR is below 30mls/min.26 A number are also metabolised via the liver p450 enzyme complex so have a number of drug interactions.27 They have no specific antidote and guidelines for use are appearing frequently. Their place as antithrombotics and in stopping and starting with other anticoagulants and co-use with anticoagulants and fibrinolytics is still under study and the manufacturer's guidance has to be studied.
Factor 10 inhibitors
Action: There are two currently available, rivaroxaban and apixaban orally and one available by sc injection, fondaparinux. They act by inhibiting F10 which prevents the cleavage of prothrombin to thrombin. Orally they offer an alternative to patients for whom warfarin is difficult to take, particularly an elderly patient coping well with a MDS for whom a stable daily dose is very helpful and those for whom INR testing or the dietary restrictions of warfarin are problematic.
Action: There were 15,700 prescriptions dispensed for rivaroxaban in 2012 costing £799,200. 30 x 10mg tablets costs £63 and it is also supplied as 15mg and 20mg tablets.13
Side-effects: It is renal metabolised, a third is eliminated by the kidneys unchanged.28 Caution is required if eGFR is below 30mls/min. It is metabolised by the CYP450 liver enzyme complex so susceptible to a number of drug interactions. It is contraindicated like all anticoagulants in patients with an increased bleeding risk, peptic ulcer, liver disease and uncontrolled hypertension. In trials the risk of bleeding was over 5%. The most common side-effect is nausea.
• DVT and PE thromboprophylaxis following knee replacement surgery in adults 10mg a day for 10-14 days.
• DVT and PE thromboprophylaxis following hip replacement surgery in adults 10mg a day for 4-5 weeks.
• DVT and PE treatment and thromboprophylaxis in adults. It performed as well as LMWH and warfarin with similar bleeding event rates, was cost effective and more convenient to patients. It allows dosing in MDS.27 Treatment dosage is 15mg bd with food for 21 days then 20mg a day.
• Non valvular AF thromboprophylaxis for CVA and systemic emboli at 20mg od with food for patients as an alternative to warfarin.
Action and side-effects as rivaroxaban. 2.5mg tablets x 60 costs £65.90. The dose is reduced in the elderly over 80 years old and those weighing 60kg or less.
• DVT and PE thromboprophylaxis following knee replacement surgery in adults, 2.5mg bd for 10-14 days.
• DVT and PE thromboprophylaxis following hip replacement surgery in adults, 2.5mg bd for 32-38 days.
• Non valvular AF thromboprophylaxis for CVA and systemic embolism as an alternative to warfarin.
There were 1,100 prescriptions for fondaparinux dispensed in 2012 and costing £227,300.1 It is given by sc injection. Patients should weigh over 50kg.
• DVT and PE thromboprophylaxis after surgery 2.5mg od.
• DVT and PE thromboprophylaxis in high risk medical patients 2.5mg sc od.
• DVT and PE treatment as an alternative to LMWH. The dosage depends upon the patient's body weight and usually continued for about five days until the warfarin has reached therapeutic levels.
• Superficial-vein thrombosis treatment 2.5mg sc od for at least 30 days (max. 45 days if high risk of thromboembolic complications); treatment should be stopped 24 hours before surgery and restarted at least six hours post operatively.
• Unstable angina (UA) and NSTEMI, 2.5mg sc od for up to eight days (or until hospital discharge if sooner); treatment should be stopped 24 hours before CABG and restarted 48 hours post operatively.
• STEMI, initially by intravenous injection or infusion then 2.5mg sc od for up to eight days (or until hospital discharge if sooner); treatment should be stopped 24 hours before CABG and restarted 48 hours post operatively.
Action: This oral drug inhibits thrombin and so prevents fibrinogen cleaving to fibrin, inactivates F13 to prevent fibrin cross-linking and so prevents platelet aggregation on fibrin. There were 48,300 prescriptions dispensed costing £2,922,100 in 2012 in the UK.1 Currently 150mg x 60 costs £665.
Side-effects: It may cause nausea and dyspepsia. Caution should be taken in patients with renal impairment, increased bleeding tendency and liver disease and if their body weight is below 50kg. It will have other liver drug metabolised interactions and there are dosage changes if the patient is also on amiodarone or verapamil. The dose is reduced in the elderly.
• DVT and PE thromboprophylaxis following total knee replacement for nine days.
• DVT and PE thromboprophylaxis following total hip replacement surgery for 27-34 days.
• Non valvular AF as thromboprophylaxis of CVA and systemic emboli as an alternative to warfarin.
Dabigatran is contraindicated in the prevention of emboli and CVA in patients with prosthetic heart valves as a clinical trial comparing dabigatran to warfarin in these patients revealed an increased risk of bleeding, mainly pericardial effusion and increased risk of thromboemboli, mainly CVAs compared to warfarin.30
This is a thrombin inhibitor used IV in patients undergoing PCI in conjunction with clopidogrel and aspirin. The other two NOACs used in this circumstance, prasugrel and ticagrelor are used with aspirin and heparin.31 It therefore also has a specific use in patients prone to HIT or HITT (see heparin above). Risks of major bleeding in trials were about 5% but of minor significant bleeding about 25%. The risks and benefits of PCI combinations are discussed in part 3 of this series.
Antiplatelets via the GP 11B/111A receptor
These drugs are currently only available IV and are given in secondary care with heparin and aspirin for patients awaiting PCI. Activation of glycoprotein receptors (GP 11B/111A) are an essential step in the aggregation of platelets so inhibition prevents platelet aggregation.
Abciximab is a monoclonal antibody32 (hence the name ending with -ab) which binds to GP 11B/111A on platelets. It is recommended to be used once only as there is a high risk of low platelets (incidence of 2%) and anaphylaxis, possibly related to its origin as a mix (chimeric) antibody derived from mouse and human (human-murine).
This is also used to prevent early MI in secondary care cardiology centres. It is given IV to treat patients with ACS (unstable angina/NSTEMI), including patients who are to be managed medically and those undergoing PCI. It can also be used in intracoronary stenting during PCI.33 Thrombocytopenia is also a serious side-effect of use though bleeding and hypotension were the two most commonly found in trials. There was no apparent difference in efficacy between older and younger patients treated with eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the risk of bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50kg.
Tirofiban is another IV option to prevent early MI in secondary care cardiology centres with heparin and aspirin and before PCI in patients with uncontrolled angina or NSTEMI.13
Antiplatelets via ADP
102,500 prescriptions were dispensed in 2012 costing £5,682,400.1 It inhibits ADP which is needed to activate platelets and in this sense is like clopidogrel and is also a prodrug, needing liver cytochrome p450 enzymes to activate. It is an oral medication given as 10mg od for 12 months post MI and there is an increased risk of bleeding with patients over 75 years old and weighing less than 60kg. In a head to head trial with aspirin and clopidogrel versus prasugrel and aspirin then in high risk patients prasugrel reduced secondary rates of MI (7.3% compared with 9.5%, p<0.001) with similar rates of death from MI or CVA. Rates of death from bleeding however were higher at 0.4% in the prasugrel group and 0.1% in the clopidogrel group (p = 0.002).34
• ACS with aspirin to prevent thrombosis in patients undergoing PCI for STEMI.
• Used with aspirin to prevent thrombosis in patients with ACS undergoing PCI when stent thrombosis has occurred in a patient who is already taking clopidogrel.
• Used with aspirin to prevent thrombosis in patients with ACS undergoing PCI when the patient has diabetes.34
This is an oral ADP receptor antagonist so prevents platelet aggregation. It's comparators are clopidogrel and prasugrel but it has only been trialled against clopidogrel. There were 28,300 prescriptions dispensed in 2012 costing £1,508,300.1 28 days treatment at 90mg bd costs £55. In trials against aspirin and clopidogrel it showed improved patient outcomes with reduced rates of MI and reduced death from vascular causes. There were similar bleeding rates over 12 months of trial. However a number of patients stopped therapy due to breathlessness.
Side-effects: Breathlessness and bleeding are the commonest side-effects. As it is also liver metabolised so medication interactions need exploring but it is contraindicated with clarithromycin.
• Given for 12 months with aspirin for patients with STEMI having PCI.
• NSTEMI. Started in secondary care hospitalised patients with unstable angina with a number of other indicators of atheroma33 which are: age 60 years or older, past MI or CABG, CHD with stenosis of 50% or more in at least two vessels, past thrombotic CVA, or TIA, carotid artery stenosis of at least 50%, past cerebral revascularisation, diabetes, PAD, CKD over less then EGFR 60mls/min.
Conflict of interest: none declared
References available on request